Cultures of peripheral blood leukocytes from a series of human donors were stimulated in vitro against TNP-modified autologous leukocytes. Proliferative and cytotoxic T cells were obtained after primary, secondary and tertiary in vitro stimulation. The cytotoxic effectors exhibited TNP-dependent activity against modified human but not against modified murine lymphocytes. The T cells recognize TNP in association with human-specific self determinants. These determinants have been classified into three groups based on studies of direct lysis and cold target cell inhibition using panels of effectors from family members and unrelated donors. One class is polymorphic and associated with serologically defined HLA-A and -B locus antigens. A second class is not strongly associated with these antigens but was polymorphic and HLA-linked. A third class of "public" determinants exists for which there was little if any polymorphism among the donors studied. This suggests that T cells recognize a variety of self-determinants in association with TNP.